This research proposal describes the convergent synthetic designs for psymberin and several structural hybrids to determine the structural origin of the unique, selective, highly potent cytotoxicity exhibited by this pederin natural product. The specific design of the structural hybrids will test whether the top acyclic side chain and central pyran core are the essential features and determine a simplified, easily accessable analogue for development. The enantioselective hetero-Diels-Alder cycloaddition is the key transformation for rapid generation of either highly substituted gem-dimethyl pyran core featured in the pederin family with the desired lower side chain intact. Biological evaluation of psymberin and the structural hybrids is proposed against several tumor cell lines. In addition, the protein binding partner(s) of psymberin and the structural hybrids will be determined by affinity chromatography. [unreadable] [unreadable] [unreadable]